1. Field of the Invention
The present invention relates to a percutaneous pharmaceutical preparation in tape form that contains estradiol and/or the esters thereof as active ingredients and permits administration of the said active ingredients by percutaneous absorption. In particular, the present invention relates to a percutaneous pharmaceutical preparation in tape form that is excellent in both release and transfer via the skin of the active ingredients, and that can provide sustained stable concentrations of the said active ingredients in the blood.
2. Description of the Prior Art
Estradiol and its esters are known as a type of female hormone which is effective for pharmacological treatment of gynecological disorders such as climacteric disturbances and menstrual abnormalities. However, owing to a high rate of hepatic metabolization, the oral administration of these drugs places a severe load upon the liver, and metabolization markedly reduces the bioavailability of the drug. Therefore, this type of drug is ordinarily administered by injection. However, although injection induces a transient elevation of the drug concentration in blood, the said concentration is not sustained over a long period, and consequently frequent administration is necessary. Hence, the use of pharmaceutical preparations with slow release is desirable, for example, preparations of a percutaneous administration type are regarded as appropriate for this purpose. However, because the skin possesses the function of preventing the intrusion of foreign matter into the body, the administration of adequate amounts of drugs by the percutaneous route is generally difficult. In order to cope with this difficulty, the area of percutaneous pharmaceutical preparation in tape form is enlarged, or various agents which accelerate percutaneous absorption are included in the preparation. Nevertheless, the drug release capabilities of such preparations cannot be regarded as adequate.
For achieving more effective percutaneous administration of estradiol or its esters, a multilayered pharmaceutical preparation is proposed in Japanese Laid-Open Patent Publication No. 57-154122. This preparation consists of a backing upon which are successively superimposed a layer that contains an active ingredient, a diffusion membrane and a pressure sensitive adhesive layer. The layer containing an active ingredient is composed of a drug gel containing estradiol dispersed in a gel formed by gelation of hydroxypropyl cellulose, etc., with ethanol. The active ingredient together with the ethanol penetrate the diffusion membrane and the pressure sensitive adhesive layer, and are then absorbed through the skin. Ethanol penetrates the skin at the rate of approximately 100-800 mcg/hr/cm.sup.2, and therefore the percutaneous absorption of the active ingredient dissolved in the ethanol is enhanced. Thus, the release of the active ingredient can be controlled by adjusting the amount of ethanol used, etc. However, because this type of preparation is multilayered, the manufacturing process of the preparation is complex, moreover, owing to the thickness of the patch, attachment to the skin causes an unpleasant feeling. Furthermore, owing to the volatility of the ethanol used, the capability of releasing the active ingredient changes during storage or after attachment of the preparation, and the releasing capability decreases with time after attachment of the preparation. Also, because ethanol irritates the skin, attachment of such a preparation is likely to cause dermal symptoms such as erythema, etc. Furthermore, due to the interposition of the diffusion membrane that functions as a control membrane, the release of ethanol and the active ingredient is insufficient, and a comparatively large area of the preparation is necessary in order to achieve satisfactory pharmacological effect.
Japanese Laid-Open Patent Publication No. 61-155321 discloses a percutaneous pharmaceutical preparation, in which an adhesive layer containing estradiol is formed on a backing, the principal components of the adhesive base material in the adhesive layer being rubber, an adhesive resin material and a polymer such as galactomannan which swells in water. This type of preparation is not unduly bulky like the above-mentioned multilayered preparation, and can provide a relatively stable delivery of the active ingredient over a prescribed period of time. Nevertheless, the overall drug-releasing capability of this preparation still cannot be regarded as adequate.